Graham Pawelec ¹, Ed Remarque ², Yvonne Barnett ³, Rafael Solana ⁴

1 University of Tübingen, Tübingen, FRG ², University of Leiden, Leiden, Holland ³, University of Ulster, Coleraine, Northern Ireland ⁴, University of Córdoba, Córdoba, Spain

Received 12/29/97 Accepted 1/5/97

9. CLINICAL RELEVANCE OF IMMUNOSENESCENCE

Decreased T cell function in the elderly is shown most clearly in vivo by DTH tests to recall antigens (269) as well as to clinically relevant immunization procedures where T cell-dependent antibody production is depressed, eg. see refs. (270,271). Antibody responses following primary immunizations in the elderly are often reported to be decreased. However, immune responsiveness to the primary antigen Helix pomatia haemocyanin (HPH) was retained in healthy elderly SENIEURS (272). By contrast, elderly subjects not fulfilling the SENIEUR criteria had a decreased immune responsiveness to HPH.

Vaccination may also have a less long-lasting effect in older donors (273). Responses to secondary antigens may normalize after boosting in elderly donors, but the improved response is not sustained for the same duration as in the young (274). Consistent with this, the majority (62%) of elderly individuals vaccinated with tetanus had antibodies to tetanus up to 10 years after vaccination, but this halved (to 33%) for vaccination more than 10 years previously. In contrast, almost all young donors retained tetanus antibodies even > 10 years after vaccination (275).

There may be more subtle differences between the responses of young and old individuals, such as a selective impairment of particular classes of antibody production, for example, of IgG1 responses to inactivated influenza virus vaccine in the elderly (276,277). This possibly reflects less efficient or altered T cell help. This shift in immunoglobulin (sub)class distribution may be a reflection of altered cytokine patterns. The response to influenza vaccination may also be highly dependent on the ´flu strain involved, as several authors have shown (278-282). They found that while the majority of elderly people responded to strains of the influenza A H3N2 subtype, few responded to strains of the influenza A H1N1 subtype (278-282). These findings are probably due to pre-exposure of the elderly and young to different strains of ´flu viruses (283). The elderly may have lower IL-2 production following in vitro stimulation with ´flu vaccine as was shown by McElhaney et al . (284). Subcutaneous low-dose IL 2 treatment prior to vaccination has been reported to enhance protection of the elderly to ´flu (285). Similar findings concerning antibody titer (but not lymphoproliferative responses) have been reported for tetanus toxoid vaccination (286). Another study has examined IgG responses of the elderly to pneumococcal vaccination and found no decrease in the old 4 - 6 weeks after vaccination with Streptococcus pneumoniae (287). Another recent study of the efficacy of ´flu vaccinations in the elderly found that annually repeated vaccination resulted in an improvement of humoral responses to several virus strains, rather than a decrease that might be predicted from clonal senescence (288). Thus, it may also be the case that in those studies where poorer responses of the elderly to vaccination were observed, this may reflect their state of health and consumption of medication more than anything else. This was illustrated in a recent study on ´flu vaccination, where response was correlated with the well-being of the vaccinees as assessed according to activities of daily living (ADL) scale (289) and in a study on responses to hepatitis B vaccination (290). However, it could also be that the 4 - 6 week period examined after immunization is not long enough to be informative. For example, old mice did not show a decline in antibody responses after an immunization with Streptococcus pneumoniae, but nonetheless, after a second immunization, the old mice showed a marked decrease in antibody production compared to the young. This was traced to a defective function of CD4⁺ T cells (291).

However, despite these findings, it remains the case that the precise clinical relevance of T cell immunosenescence is hard to define. Indeed, there are studies suggesting that it is the NK status of subjects which is critical; Ogata et al . recently reported that not the numbers but the functional activity of NK cells was the only parameter correlating with death (due to infection) in the follow-up period (292). However, they did not test T cell function, only numbers. Inclusion of T cell functional parameters has been shown to predict mortality in a Swedish prospective study (8). In mice, there are several models where age-associated alterations in immune responsiveness correlate with a decreased ability to cope with infection, eg. by trypanosomes (293). In human, Varicella zoster reactivation is commonly quoted in support of the relevance of immunosenescence, and specific abnormalities in anti-viral immunity have been distinguished in the elderly in some studies (294). For example, the well-known age-associated increased incidence of shingles in the elderly is associated with a decrease in the frequency of VSV-specific T cells which produce IFN-g and decreased amounts secreted compared to young immune donors. On the other hand, the production of IL 4 in the same donors was unchanged (295). Correspondingly, antibody levels to VSV are maintained in the elderly, but this is clearly not always enough to prevent reactivation of infection. These data suggest that the general state of health is not the only factor contributing to depressed immunity. On the other hand, the similarity of some infection- or cancer-induced and aging-induced changes can be striking. Moreover, these changes may be additive, resulting in severe clinical manifestations. Thus, Utsuyama et al . (293) reported that Trypanosoma musculi-infected mice exhibited a rapid change in the CD4⁺ population in the direction of memory/activation with decreased cytokine production; this was associated with clearing of infection; however, old mice already having this phenotype were barely able or unable to clear the infection.

Autopsy data on the very old suggest that the accepted prime age-associated causes of death in the "younger old" (ie. cardiovascular disease, cancer) do not necessarily apply to the very old. Studies from Leiden, Geneva and Tokyo have found the prime cause of death to be infectious disease in the over 80´s (however, whether these were really opportunistic infections is still not clear). An extensive study on major causes of death in Japan between 1951 and 1990 suggests that unlike those causes showing deceleration or neutrality with advancing age, those showing acceleration in old age (ie. pneumonia, influenza, gastroenteritis, bronchitis) mostly involve infectious agents (296). According to some data, a major predictor of mortality in the elderly is lung function (297). Immunosenescence may also play an important role here, since the defense of this most common pathogen entry portal is critical. In support of this concept, Meyer et al . (298) have provided evidence for immune dysregulation in the aging human lung. On the other hand, allergic reactions may decrease with age for the same reason, as with the well-known "growing out" of asthma. In a rat model of asthma, it was found that the level of specific IgE antibody and eosinophils in bronchoalveolar lavage was markedly higher in young rats. This correlated with increased interferon-g production and decreased IL 5 in old rats T cells (299).